Cardiac arrhythmia is a major cause of mortality in cardiovascular pathologies. Aberrancies in cardiac Ca2+ signaling have been associated with development of arrhythmia. For instance, it has been found that leaky ryanodine receptors elevate local Ca2+ concentrations causing membrane depolarizations that trigger arrhythmias. Increases in frequency of Ca2+ sparks that trigger Ca2+ waves are known to activate depolarizing currents responsible for early or late after-depolarizations and arrhythmias. Due to such findings, Ca2+ signaling has been a primary target of antiarrhythmic pharmacotherapy. In fact, inhibition of the spontaneous release of Ca2+ (e.g., via leaky ryanodine receptors) is proposed to be critical in the pharmacotherapy of arrhythmias, as reported recently for clinical use of flecainide.
The regulation of Ca2+ release from the sarcoplasmic reticulum (SR) is mediated not only by binding of Ca2+ to ryanodine receptor 2 (RyR2), but also by a host of regulatory proteins that include calmodulin, protein kinase A, FK506-binding protein (FKBP12.6), Ca2+/calmodulin-dependent protein kinase II, protein phosphatases (calcineurin), and junctional and luminal SR proteins junctin, triadin, and calsequestrin. In addition, mitochondrial-derived reactive oxygen species (ROS) have been reported to modulate RyR2-mediated Ca2+ spark activity, supporting the possibility that local control of SR Ca2+ release is regulated partially by mitochondrial ROS production. In ischemia-reperfusion-induced arrhythmias, experimental evidence also suggests deleterious effects arising from mitochondrial Ca2+ overload, ROS generation, and opening of permeability transition pores that leads to overactive RyR2 activity, causing local membrane depolarizations. It has been suggested that these depolarizations propagate from cell to cell and can be effectively suppressed by free oxygen radical scavengers.
Xanthohumol, a prenylated chalcone, is one of the principal flavonoids present in hop plant cone extracts. Flavonoids have been reported to have therapeutic effects as an antiproliferative in human breast cancer, colon cancer, and ovarian cancer, and in preventing cancerous cell growth through inhibition of cytochrome P450 enzymes. Xanthohumol has also been suggested to counteract low-density lipoprotein-induced oxygen-damaging effects, improve neuronal plasticity, and produce therapeutic effects against arteriosclerosis and osteoporosis.
Unfortunately, a host of drugs targeted to sarcolemmal Na+, Ca2+, and K+ channels for antiarrhythmic pharmocotherapy have had limited clinical success. What is needed in the field are agents that can be effective in reducing the cardiomyocyte Ca2+ leak that leads to arrhythmia.